Dual pH/ROS-Responsive Nanoplatform with Deep Tumor Penetration and Self-Amplified Drug Release for Enhancing Tumor Chemotherapeutic Efficacy.

Poor deep tumor penetration and incomplete intracellular drug release remain challenges for antitumor nanomedicine application in clinical settings. Herein, a nanomedicine (RLPA-NPs) is developed that can achieve prolonged blood circulation, deep tumor penetration, active-targeting of cancer cells, endosome/lysosome escape, and intracellular selectivity self-amplified drug release for effective drug delivery. The RLPA-NPs are constructed by encapsulation of a pH-sensitive polymer octadecylamine-poly(aspartate-1-(3-aminopropyl) imidazole) (OA-P(Asp-API)) and a ROS-generation agent, ß-Lapachone (Lap), in micelles assembled by the tumor-penetration peptide internalizing RGD (iRGD)-modified ROS-responsive paclitaxel (PTX)-prodrug. iRGD could promote RLPA-NPs penetration into deep tumor tissue, and specific targeting to cancer cells. After internalization by cancer cells through receptor-mediated endocytosis, OA-P(Asp-API) can rapidly protonate in the endosome's acidic environment, resulting in RLPA-NPs escape from the endosome through the "proton sponge effect". At the same time, the RLPA-NPs micelle disassembles, releasing Lap and PTX-prodrug. Subsequently, the released Lap could generate ROS, consequently amplifying and accelerating PTX release to kill tumor cells. The in vitro and in vivo studies demonstrated that RLPA-NPs can significantly improve the therapeutic effect compared to control groups. Therefore, RLPA-NPs are a promising nanoplatform for overcoming multiple physiological and pathological barriers to enhance drug delivery.

Diselenium-linked dimeric prodrug nanomedicine breaking the intracellular redox balance for triple-negative breast cancer targeted therapy.

Triple-negative breast cancer (TNBC) has been regarded as the strongest malignancy in cases of breast cancer with a poor prognosis. The development of effective treatment strategies for TNBC has always been an urgent and unmet need. The intracellular redox balance is essential for maintaining TNBC cell malignancy. Disrupting intracellular redox balance by enlarging reactive oxygen species (ROS) generation and facilitating glutathione (GSH) depletion to amplify intracellular oxidative stress may be an alternative strategy to eliminate TNBC cells. However, inducing ROS generation and GSH depletion concurrently may be challenging. Herein, a diselenium linked-dimeric prodrug nanomedicine FA-SeSe-NPs was developed to break the intracellular redox homeostasis for TNBC targeted therapy. The dimeric prodrug was synthesized by conjugating two cucurbitacin B (CuB) molecules via one diselenium bond, which was subsequently assembled with FA-PEG-DSPE to form the final nanomedicine FA-SeSe-NPs. Using the active targeting potential of folic acid (FA), FA-SeSe-NPs could accumulate in tumor tissue with elevated levels and then be specifically internalized by cancer cells. In the high ROS and GSH conditions of TNBC cells, the diselenium bond can specifically respond to ROS to produce selenium free radicals to increase ROS and react with GSH to generate S-Se bond to deplete GSH. The released CuB further induced ROS production in TNBC cells. The diselenium bond and CuB functioned synergistically to amplify oxidative stress to kill the TNBC cells. Here, we provide a promising strategy to disrupt the intracellular redox balance of cancer cells for effective TNBC therapy.

Transferrin receptor-targeted redox/pH-sensitive podophyllotoxin prodrug micelles for multidrug-resistant breast cancer therapy.

Podophyllotoxin (PPT), a toxic polyphenol extracted from the roots of Podophyllum species, showed remarkable activity against P-glycoprotein (P-gp) mediated multidrug resistant (MDR) cancer cells. Many PPT-prodrugs based on nano-technology have been developed for increasing aqueous solubility and reducing the side effects of PPT; however, the sensitive linkers in almost all PPT-prodrugs were ester bonds, resulting in slow and incomplete drug release. We developed a redox/pH double-sensitive and tumor active targeted drug delivery system for PPT delivery, in which PPT was covalently coupled to T7-peptide (Pep) modified polyethylene glycol (PEG) or methoxy-polyethylene glycol (mPEG) through a disulfide bond to obtain the final polymer (Pep-PEG-SS-PPT or PEG-SS-PPT). The mixed micelles (Pep-SS-NPs) were made by mixing Pep-PEG-SS-PPT with PEG-SS-PPT, and the mixed micelles showed good size uniformity and high stability in serum solution. The in vitro release experiment showed that about (81.7 ± 2.8)% PPT was released from Pep-SS-NPs in 10 mM glutathione (GSH) at pH 7.4, and also about (64.6 ± 1.7)% PPT was released from Pep-SS-NPs at pH 5.0. In vitro cytotoxicity analysis suggested that Pep-SS-NPs exhibited 57- to 270-fold lower resistance index (RI) values for different drug-resistant cancer cell lines than paclitaxel (PTX) or docetaxel (DTX). The cell uptake assay indicated that the Pep-SS-NPs could significantly enhance the intracellular level of coumarin-6 compared to that of the control group. The maximum tolerated dose (MTD) of Pep-SS-NPs was increased greatly compared to that of free PPT (5.3-fold). In vivo research showed that Pep-SS-NPs significantly enhanced antitumor efficacy against MCF-7/ADR xenograft tumors compared to the control groups. These findings suggest that mixed micelles could be a potentially successful nanomedicine for MDR breast cancer therapy.